tbuckley/cabot-search huggingface dataset:
Radiologic features of immune checkpoint inhibitor-related nephritis with clinical correlation in biopsy-proven cases.
Authors: Muhammad Awiwi, Ala Abudayyeh, Noha Abdel-Wahab, Adi Diab, Migena Gjoni, Guofan Xu, Raghu Vikram, Khaled M. Elsayes
Journal: Journal of Clinical Oncology (2022)

e14585 Background: Radiologic findings associated with biopsy proven immune checkpoint inhibitor (ICI) related nephritis have not been described. The objective of this study is to describe the radiologic features of immunotherapy related nephritis on computerized tomography (CT) and positron emission tomography (PET). A secondary objective is to investigate the association of these radiologic features with renal outcomes. Methods: A retrospective review of all biopsy proven ICI-related nephritis between February 2017 and April 2021 was performed and 34 patients were identified. CT and PET-CT scans before the initiation of immune checkpoint inhibitors (baseline), at nephritis and after resolution of nephritis were reviewed. Total kidney volume, renal parenchymal SUVmax, renal pelvis SUVmax and blood pool SUVmean were obtained. Results: The total kidney volume was significantly higher at nephritis compared to baseline (464.7±96.8 mL vs. 371.7±187.7 mL; p &lt; 0.001). Fifteen patients (44.1%) had &gt; 30% increase in total kidney volume at nephritis. A &gt; 30% increase in total kidney volume was associated with significantly higher renal toxicity grade (p = 0.007), higher peak creatinine level (p = 0.004) and more aggressive medical treatment (p = 0.011). New/increasing perinephric fat stranding was noted in 10 patients (29.4%) at nephritis. Among 8 patients with contrast-enhanced CT at nephritis, 1 patient (12.5%) developed bilateral wedge-shaped hypoenhancing cortical lesions that healed with focal scarring on subsequent scans. On PET-CT, the renal parenchymal SUVmax-to-blood pool SUVmean ratio was significantly higher at nephritis compared to baseline (2.13 vs. 1.68; p = 0.035). The renal pelvis SUVmax-to-blood pool SUVmean ratio was significantly lower at nephritis compered to baseline (3.47 vs. 8.22; p = 0.011). Conclusions: Bilateral increase in kidney size, new/increasing perinephric stranding and bilateral wedge-shaped hypoenhancing cortical lesions can occur in immunotherapy-related nephritis. On PET-CT, diffuse bilateral increase in radiotracer uptake throughout the renal cortex and decrease in radiotracer activity in the renal pelvis can be seen. A &gt; 30% increase in total kidney volume was associated with significantly higher renal toxicity grade and more aggressive medical treatment in a subset of patients. Acknowledgment: National Institute of Health K01 Award (N.A.: K01AI163412).
A phase 2 study of cabozantinib in combination with atezolizumab as neoadjuvant treatment for muscle-invasive bladder cancer (HCRN GU18-343) ABATE study.
Authors: Deepak Kilari, Aniko Szabo, Abhishek Tripathi, Asit K. Paul, Robert S. Alter, Kathryn A. Bylow, Ariel Ann Nelson, William A. Hall, Peter Langenstroer, Kenneth Jacobsohn, Brian I. Rini, Peter J. Van Veldhuizen, Scott Johnson, Nancy B. Davis, Chunkit Fung, Matthew I. Milowsky
Journal: Journal of Clinical Oncology (2022)

TPS4618 Background: ABACUS and PURE-01 trials demonstrated the activity of single agent atezolizumab and pembrolizumab respectively as neoadjuvant therapy for muscle invasive bladder carcinoma (MIBC). However, downstaging to non-muscle invasive disease was noted in only 50 percent of patients. Resistance to programmed death (PD)- 1/L1 antibodies is likely to include factors such as impaired dendritic cell maturation/function, infiltration of T-Regs and myeloid derived suppressor cells, impaired T-cell priming and T-cell trafficking in tumors. Cabozantinib is a tyrosine kinase inhibitor which targets MET, AXL, MER, Tyro3 and VEGFR2. Cabozantinib has a unique immunomodulatory profile and has demonstrated clinical activity as monotherapy and in combination with PD-1/L1 antibodies in various solid tumors including urothelial cancer (UC), renal cell, castrate- resistant prostate and non-small cell lung cancer. We hypothesize that the combination of cabozantinib and atezolizumab as neoadjuvant therapy for MIBC would improve rates of pathologic downstaging compared to single-agent checkpoint inhibitors. Methods: ABATE is an open-label, single arm, multi-center study to assess the efficacy and safety of cabozantinib with atezolizumab as neoadjuvant therapy for cT2-T4aN0/xM0 MIBC. An estimated 42 patients will be enrolled to obtain 38 evaluable patients, and the study will have over 80% power to declare the investigational combination to be successful using a Bayesian evaluation at 90% posterior probability cutoff, if the response probability is 59%, i.e., 20% higher than the 39% response rate with the single agent atezolizumab. Eligible patients will receive cabozantinib 40 mg PO daily with atezolizumab 1200mg every 3 weeks for a total duration of 9 weeks (3 cycles) followed by radical cystectomy. Adults (≥18 years) with resectable MIBC who are either cisplatin-ineligible or decline cisplatin-based chemotherapy are eligible. Patients are required to have an ECOG PS of 0-2 and provide tumor tissue for PD-L1 expression analysis. UC should be predominant component (≥ 50%). Previous systemic anticancer therapies for MIBC are not permitted. CT/MRI will be performed before investigational therapy and cystectomy. Primary endpoint is pathologic response rate defined as the absence of residual muscle-invasive cancer in the surgical specimen (&lt; pT2). Secondary endpoints are safety and toxicity, pathologic complete response rate and event-free survival. Exploratory end points include patient-reported outcomes and outcome associations with biomarkers. Accrual began May 2020. Clinical trial information: NCT04289779.
Trial in progress: A phase II switch maintenance study of live biotherapeutic MRx0518 and avelumab in patients with unresectable locally advanced or metastatic urothelial carcinoma (UC) who did not progress on first-line platinum-containing chemotherapy.
Authors: Amishi Yogesh Shah, Jianjun Gao, Arash Rezazadeh, Suzanne Cole, Rohit K. Jain, Alex Stevenson, Gayle Fyvie, Nina Jane Gaw, Shubham Pant
Journal: Journal of Clinical Oncology (2022)

TPS4610 Background: Efficacy of avelumab for maintenance treatment of UC was investigated in the JAVELIN Bladder 100 study (NCT02603432), which led to the FDA approval of avelumab for maintenance treatment as the current standard of care for patients with locally advanced or metastatic UC that have not progressed with first-line platinum-based chemotherapy. Outcomes included median overall survival (OS) of 21.4 months (95% CI 0.56-0.86), median progression-free survival (PFS) of 3.7 months (95% CI 3.5-5.5) and objective response rate (ORR) of 9.7% (95% CI 6.8-13). MRx0518 is a novel, human gut microbiome-derived, single-strain, live biotherapeutic. It is a bacterium of the Enterococcus genus that was selected for development in solid tumor treatment for its strong in vitro and in vivo immunostimulatory activity. In vivo studies have shown that MRx0518 can inhibit tumor growth in different syngeneic cancer models as both monotherapy and in combination with immune checkpoint inhibitors. MRx0518 has been shown to reduce Treg and increase Th1 and Tc1 lymphocyte differentiation in vitro and increase intratumoral CD4+ and CD8+ T cells and NK cells in vivo. In clinical studies, preliminary data shows that MRx0518 monotherapy can increase anti-tumor TILs and systemic pro-inflammatory immune signaling molecules. This is a pilot study evaluating whether the addition of MRx0518 to avelumab in the maintenance setting of metastatic platinum-treated UC may improve outcomes. Methods: The study will enroll 30 patients with unresectable locally advanced or metastatic UC at multiple US centers. Patients must have measurable disease after a partial response or stable disease on 4-6 cycles of platinum-containing induction chemotherapy. Patients will receive 800 mg avelumab IV infusion every 2 weeks in combination with 1 oral capsule (10x10 10 – 10x10 11 CFU) MRx0518 twice daily until disease progression, patient withdrawal or unacceptable toxicity. Primary objectives are to assess safety of the combination, and effect on PFS at 6 months. Secondary objectives are to assess other efficacy measures including PFS, ORR, OS, duration of response, time to response, and disease control rate. Collection of paired research biopsies at baseline (after chemotherapy) and on treatment (after 8 weeks of MRx0518 + avelumab), plus longitudinal blood sampling, will allow investigation of immunological changes systemically both in the tumor and as potential predictive markers of response. Stool and urine samples collected before, during and after treatment will allow investigation of changes to the microbiome and metabolome. Recruitment is open, awaiting accrual. Clinical trial information: NCT05107427.
A prospective real-world study to assess the effectiveness and safety of trastuzumab biosimilar in the adjuvant treatment of HER2-positive breast cancer: Preliminary safety results.
Authors: Ana Carolina Ferreira Cardoso, Debora De Melo Gagliato, Natália Mesquita Brito, Maura Gonzaga Lapa, Érida Aparecida Pinto Magaton, Renata Virgínia Cavalcanti Santos, Vivienne Carduz Castilho
Journal: Journal of Clinical Oncology (2022)

e12524 Background: The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) defines a biosimilar as a biological molecule product that is highly similar to and has no clinically meaningful differences from an existing approved reference product. The trastuzumab biosimilar was the first oncology biosimilar approved in Brazil for HER2-positive breast cancer (BC) and advanced gastric cancer treatment. This study aimed to assess the effectiveness and safety of trastuzumab biosimilar (named as Zedora in Brazil) in the adjuvant setting among HER2-positive BC patients treated in Brazil. Methods: This is a national, multicentric, observational, and prospective real-world study. Patients with early-stage HER2-positive BC who received at least one dose of trastuzumab biosimilar as adjuvant therapy were eligible. At the present date, 126 of 170 planned patients were recruited. Here, we present the preliminary safety data of the first 42 patients recruited in the study. The safety endpoint is the occurrence of adverse events (AEs), and the safety population included all patients who received at least one dose of trastuzumab biosimilar. We analyzed the AEs collected from the signature of the consent form until the end of adjuvant treatment. Results: Baseline patient characteristics among the 42 evaluated patients included a median age of 48.5 years, with 78.6% of them having a node-negative disease. Most patients had hormone-receptor-positive tumors (71.4% estrogen-receptor-positive and 57.1% progesterone-receptor-positive). The number of patients undergoing conservative surgery (59.5%) was higher than mastectomy (40.5%). The most frequent histological BC subtype was invasive ductal carcinoma (97.6%). Neoadjuvant therapy included the trastuzumab biosimilar administration (25%) and the dual anti-HER2 block (trastuzumab biosimilar + pertuzumab) (68.8%). Only 6.3% of patients received the reference trastuzumab in neoadjuvant therapy. In total, 25/42 (59,5%) patients had at least one AE, two of them were serious AEs (4.8%). The incidence of grade 3 or 4 AEs was 35.7%, and no death occurred. The table lists the most reported AEs according to SOC (System Organ Class). Conclusions: The nature and severity of AEs observed were consistent with the known safety profile of trastuzumab. Clinical trial information: NCT03892655. [Table: see text]
Impact of metastasectomy for extrahepatic disease in stage IV colon cancer: A retrospective cohort NCDB analysis.
Authors: Jesus C. Fabregas, Ilyas Sahin, Sherise C. Rogers, Brian Hemendra Ramnaraign, Ibrahim Nassour, Steven J. Hughes, Thomas J. George
Journal: Journal of Clinical Oncology (2022)

e15548 Background: Stage IV colon cancer has a dismal prognosis with a 5-yr survival rate of only 14%. The role of liver metastasectomy is well established. However, it is not clear if there is a survival benefit for metastasectomy in cases of extrahepatic disease. Methods: We conducted a retrospective cohort study, US hospital-based. The NCDB version 2017 was accessed. Exposure variable: metastasectomy for extrahepatic distant disease, analyzed as binary. Outcome: overall survival. Kaplan Meier curves and log rank test were used for survival analysis. The primary endpoint was to estimate the association between metastasectomy and survival. Covariates demographic factors, age, sex, race, insurance status, site of metastatic disease – lung, liver, bone, brain. A Cox proportional hazards model was used to evaluate the impact of metastasectomy of extrahepatic disease in patients with stage IV colon cancer. 95% confidence intervals and p values of less than 0.05 were used for statistical significance. Missing data as handled with complete and available case analysis. Statistical analysis was done using Stata 16. Results: A total of 68,334 adult patients with stage IV colon cancer diagnosed in from 2010 -2016 were included in the final analysis. Median age was 64 years (SD 14.1). Prevalence of metastases in this stage IV population was as follows: Liver 72.12%, Lung 20.12%, Bone 5.06%, Brain: 1.6%. A total of 10,595 patients (15.5%) had metastasectomy. Median overall survival were as follows: Lung, 21.59 months with surgery vs 8.41 months no surgery. Bone, 7.03 mo vs 4.53 mo respectively; Brain 9.3 mo vs 3.15 mo; Liver 33.28 mo vs 10.97 mo. In univariate analysis, patients with lung metastases had an improved survival if they had metastasectomy (vs no surgery, HR 0.58, p &lt; 0.0001, 95% CI 0.52 – 0.60). The same benefit was observed in patients with bone (HR 0.80, p 0.001, 95% CI 0.69 – 0.91) and brain metastases (HR 0.56, p &lt; 0.001, 95%CI 0.49 – 0.65). In multivariable analysis the survival advantage was still significant. In a sensitivity analysis, excluding patients with liver metastases, the improvement in survival persisted. Conclusions: Metastasectomy for extrahepatic disease improved overall survival in patients with colon cancer in this retrospective analysis. Further research is needed before routinely incorporating it in clinical practice.[Table: see text]
Safety and tolerability of T-SIGn vectors when administered using “flat” versus “low-high-high” (LHH) dosing regimens.
Authors: Thomas Lillie, Lee S. Rosen, David Krige, Minesh Patel, Isabel Prieto González-Albo, Jo Carter, Behnaz Ravanfar, Vladimir Evilevitch, Aung Naing
Journal: Journal of Clinical Oncology (2022)

2572 Background: Tumor-selective viruses, particularly those dosed systemically to deliver transgenes, are potentially powerful cancer therapies. However, acute cytokine reactions to viral particle (vp) infusion may affect vector tolerability [Small 2006], thereby limiting the maximum tolerated dose (MTD) and subsequent transgene delivery. T-SIGn vectors (e.g. NG-641 and NG-350A) are transgene-armed variants of the epithelial tumor-selective adenovirus enadenotucirev (EnAd). Acute serum cytokine increases post-dosing have been seen at the MTD of EnAd (“flat” dosing of 3 x 10 12 vp on Days [D] 1, 3 and 5) [Machiels 2019]. Following supportive preclinical data [McElwaine-Johnn 2019], we explored if a LHH dosing regimen, in which a lower dose is given on D1 prior to two higher doses on D3 and 5, may improve vector safety/tolerability thereby allowing higher cumulative doses to be given. Methods: Data were pooled from three Phase 1 dose-escalation studies in advanced/metastatic epithelial cancer: SPICE (EnAd + pembrolizumab/nivolumab; NCT02636036), FORTITUDE (NG-350A ± pembrolizumab; NCT03852511) and STAR (NG-641; NCT04053283). Serum cytokines were measured using a 17-analyte Luminex assay. IL-6/MCP-1 data for D1, 3 and 5 (pre- and 6-10 hrs post-dose) were analyzed to examine acute cytokine changes. TNFα/IFNγ were examined due to their association with cytokine release syndrome (CRS). Samples analyzed from SPICE/FORTITUDE were taken before PD-1 inhibitor administration. Results: 84 patients (SPICE n=51; FORTITUDE n=18; STAR n=15) were included in these analyses; 79 had cytokine data. AEs and Gr≥3 AEs within 1 wk of first dose, and DLTs at any time, were less frequent with a LHH vs flat dosing regimen (Tbl). Importantly, a LHH dose of 1-6-6 (1 x 10 12 vp on D1; 6 x 10 12 vp on D3 and 5; greater than the previous flat MTD) was tolerated. Acute increases in TNFα/IFNγ were limited and no severe CRS was seen. Increases in IL-6/MCP-1 with 1 x 10 11 or 1 x 10 12 vp flat dosing were negligible, whereas acute increases in IL-6/MCP-1 were seen after the first dose of 3 x 10 12 vp when given as a flat dose (negligible increases on D3/5). Notably, cytokine responses with 1-3-3 dosing (1 x 10 12 vp on D1; 3 x 10 12 vp on D3 and 5), including after the first 3 x 10 12 vp dose on D3, were negligible. Cytokine responses after the first dose of 6 x 10 12 vp in the 1-6-6 regimen were similar to those seen with the first dose of the flat 3 x 10 12 vp regimen. Conclusions: LHH dosing appears to induce a desensitization mechanism allowing higher cumulative doses of T-SIGn vectors to be given without the associated acute reactions to viral infusions. This finding may have implications for optimizing safety-efficacy profiles of viral vectors in cancer. Clinical trial information: NCT02636036, NCT03852511 and NCT04053283. [Table: see text]
The association of chromosome 11q13 amplification with the hyperprogressive disease in unresectable hepatocellular carcinoma patients underwent the immunotherapy.
Authors: Haibin Zhang, Kai Yan, Ding Zhang, Yanan Chen, Mengli Huang, Yong Fu, Wenfeng Lu
Journal: Journal of Clinical Oncology (2022)

e16156 Background: Hyperprogressive disease (HPD) is characterized by an acceleration of tumor growth during systemic therapy, which usually refers to immunotherapy. The incidence of HPD in patients with hepatocellular carcinoma (HCC) is reported to be 12.7%. Amplification of the chromosome 11q13 locus, including cyclin D1 (CCND1), FGF3, FGF4 and FGF19, is frequent in many cancers and correlates with inferior outcomes with immunotherapy. However, little is known about the association between chromosome 11q13 amplification and HPD of HCC. Methods: 58 HCC patients who underwent the next-generation sequencing (NGS) in our institution from September 2017 to April 2018 were enrolled in this study. Among them, 30 patients had unresectable advanced or recurrent HCC and received anti-tumoral therapy, including 18 cases (Group 1) receiving programmed cell death-1 (PD-1) monoclonal antibody immunotherapy (with or without tyrosine kinase inhibitors, TKIs) and 12 cases (Group 2) receiving local regional therapy (with or without TKIs). Based on radiological surveillance, HPD was defined as: 1. Tumor growth kinetics (TGK) or tumor growth rate (TGR) &gt; 2; 2. Time to treatment failure &lt; 2 months. Results: In our dataset, chromosome 11q13 amplification (11q13 Amp) was seen in 11 patients (19.0%). 11q13 Amp was associated with worse clinical baseline, with a significant concentration in patients with BCLC C stage, tumor numbers of ≥ 3 and ECOG 1 score. Group 1 had an objective response rate (ORR) of 50.0% and Group 2 had an ORR of 54.5%. There was no significant difference in progression-free survival (PFS) between these two groups. 3 patients showed HPD in Group 1, all of whom carried 11q13 Amp. Compared to non-11q13 Amp patients, patients with 11q13 Amp had worse PFS (log-rank P= 0.001) in Group 1. While there was no significant difference of PFS between 11q13 Amp and non-11q13 Amp patients in Group 2. We further investigated the efficacy of different treatment strategies based on 11q13 Amp status. These 11q13 Amp patients in Group 1 showed worse PFS, compared to Group 2 (log-rank P= 0.025). However, patients with non-11q13 Amp showed similar outcomes between these two groups (log-rank P= 0.70). Conclusions: Our findings suggested that 11q13 Amp was associated with HPD of HCC. PD-1 monoclonal antibody showed poor efficacy in patients with 11q13 Amp, therefore targeted treatment strategies might be more suitable for such patients. Meanwhile, the role of 11q13 Amp as putative predictive biomarkers of HPD needs further validation in larger cohorts.
Lenvatinib for the treatment of thymic epithelial tumors (TETs): A real-life multicenter experience.
Authors: Jose Carlos Benitez, Juan Florez-Arango, Eric Dansin, Giuseppe Giaccone, Clemence Basse, Julien Mazieres, Thomas Pierret, Matteo Giaj Levra, Elvire Pons-Tostivint, Jennifer Arrondeau, Mihaela Aldea, Pascale Missy, Thierry Molina, Nicolas Girard, Benjamin Besse
Journal: Journal of Clinical Oncology (2022)

8585 Background: TETs are rare malignancies of the anterior mediastinum being thymoma (T) B3 and thymic carcinoma (TC) the most aggressive subtypes. There is no standard treatment after platinum-based chemotherapy in refractory or metastatic setting. A phase 2 trial has reported clinical benefit for lenvatinib 24mg (objective response rate [ORR] of 38%), a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases; significant toxicity grade 3 hypertension was 64%. No real-life data exists. Methods: We selected patients (pts) under lenvatinib as a second-line or beyond for refractory TETs from 8 International centers from France (belonging to the nationwide network RYTHMIC) and United States. We analyzed epidemiologic, clinical and pathological characteristics of patients with TET’s. The toxicity was evaluated according to CTCAE v4, with a local evaluation of efficacy and we assessed toxicity profile and survival outcomes. Results: From March 2020 to December 2021, 29 pts were enrolled. Median age at diagnosis was 49 (24-71), 51.7% were women, 6/29 (20.7%) reported auto-immune disorders (AIDs). TC was the most frequent subtype (n=18, 62.1%), followed by B3 and B2. Lenvatinib was used as a second line for 52% of pts, mainly starting from 14 mg/daily (n=20, 69%) and one pts with concomitant pembrolizumab. The ORR was 17% (95%CI 3.0-32.0) with partial responses only seen in TC, and the disease control rate was 76% (95%CI 59.0-92.0). Response was observed with the dose of 24mg in 3 pts and 14mg in 2 pts, with a median follow-up period of 5 months (m) (95%CI 3.2-6.7), PFS at 6 and 12 m was 64% and 30%, respectively. Toxicity is summarized in table 1. Dose de-escalations were needed in 27.5% of pts. Conclusions: We confirm the activity of lenvatinib in pts with advanced or metastatic T and TC, despite the use of lower doses than the phase 2 study.[Table: see text]